Management of Congenital Methemoglobinemia in the Perioperative Setting: A Case Report and Review of Current Literature

Background Methemoglobin is an altered state of hemoglobin where iron in hemoglobin is oxidized and incapable of binding oxygen; leading to complications such as cyanosis, dyspnea, headache, and heart failure. Methemoglobinemia can be congenital or acquired. Congenital methemoglobinemia is a rare disease and its worldwide incidence is unclear. We recently encountered the first documented case of congenital methemoglobinemia at our institution, necessitating perioperative care. Case Presentation In the present case, a 22-year-old man with congenital methemoglobinemia underwent general anesthesia for dental extraction. The surgeon was informed to avoid local anesthetics and oxygenation was performed with FiO2 of 1.0. Arterial blood gas analysis showed a PH of 7.337, PaO2 of 302 mm Hg, PaCO2 of 44 mm Hg, oxyhemoglobin level of 63.4%, and methemoglobin level of 37.8%. The patient had a stable course. No methylene blue therapy was required, although cyanosis was observed during surgery. Conclusion In summary, though rare, congenital methemoglobinemia poses fatal risks during surgery. Its management involves preoperative recognition and optimization, oxygenation status, multidisciplinary care, avoiding precipitating or oxidizing agents, discussing treatment options, maintaining cardiopulmonary stability, and ensuring perioperative safety measures with the medical team.


Introduction
Methemoglobin (MetHb) is an altered state of hemoglobin (Hb) containing iron in the Ferric (Fe 3+ ) state rather than Ferrous (Fe 2+ ).Ferric iron cannot bind and transport oxygen.Thus these patients can develop functional anemia and tissue hypoxia.MetHb is normally present in less than 1% of the blood concentration. 1 With higher concentrations, symptoms develop.
Methemoglobinemia can be congenital and is usually rare.It can be attributed to either a cytochrome b5 reductase deficiency or the presence of hemoglobin M disease. 2 Acquired methemoglobinemia is however more common and unfortunately more severe.This condition can arise from using different pharmacological agents including nitrates, and local anesthetics such as prilocaine, dapsone, and nitroglycerine (Box 1). 3 We describe the perioperative management of a patient, diagnosed with congenital methemoglobinemia, who required general anesthesia for dental extraction.

Case Report Background
We report a 22-year-old (98 kg bodyweight, 166 cm tall, BMI 35.6) Middle Eastern male, posted for elective extraction of carious wisdom teeth under general anesthesia.He was known to have congenital methemoglobinemia as well as some The patient also has had multiple previous visits to our hospital emergency department mainly with cyanosis and associated symptoms.Most of the ED visits had culminated in him receiving methylene blue and hydroxycobalamin before being discharged.A hematologist and cardiologist's opinion had been documented in his health records.His coexisting learning disability suggested a diagnosis of Autosomal recessive congenital methemoglobinemia.Echocardiography had ruled out congenital cyanotic heart disease.

Preoperative Assessment and Optimization
Armed with the available history, our focus was on the patient's cardio-respiratory fitness.In the pre-anesthesia visit for his current surgery, our patient reassured us that he could comfortably engage in routine physical activities, including walking and climbing stairs, without experiencing headaches, palpitations, or dyspnea.
On examination, he had visible bluish discoloration of his fingers and lips.The airway assessment revealed Mallampati grade II, adequate mouth opening, and normal neck movement.Oxygen saturation (SPO2) at the time was measured only 87% on room air.Blood investigations showed secondary polycythemia (Figure 1), Glucose-6-Phosphate Dehydrogenase (G6PD) within normal levels, and methemoglobin at around 3.9-7.1% (Figure 2).
A Transthoracic Echocardiography reported mild aortic regurgitation and trivial tricuspid regurgitation.He was referred to a hematology and genetic clinic for whole exome sequencing.The hematologist opined that the patient is fit for surgery and to avoid venesection for polycythemia as it will worsen his condition.

Intraoperative Management
On arrival in the operating room, baseline SPO2 was 84%.Following five minutes of preoxygenation with 100% oxygen, induction of general anesthesia was performed with calculated doses of fentanyl (2 mcg/kg), propofol (2mg/kg), and rocuronium (1mg/kg).A 6.5 mm ID nasal endotracheal tube was inserted uneventfully and anesthesia was maintained with 100% oxygen, sevoflurane, and controlled ventilation (volume controlled, Tidal volume 450 mL, Respiratory rate 12/min, Peak airway pressure 23 mmHg, Positive end-expiratory pressure 5 mm Hg).SPO2 marginally improved to 87% on controlled ventilation and oxygenation.
An arterial line was inserted post-induction for frequent blood sampling for partial pressure of oxygen (PO2), patient acid-base balance, and methemoglobin level measurement.Invasive blood pressure monitoring was used to rapidly determine significant hemodynamic changes.The surgical team was requested to avoid lidocaine.Methylene blue was kept ready in case.
Methemoglobin level post induction was 37.8% and SPO2 was at 87% and considered inaccurate.The procedure was uneventful with no desaturation from baseline or acidosis in blood gases.

Postoperative Management
Emergence from general anesthesia and extubation was smooth.The patient was moved to the Post Anesthesia Care Unit (PACU) and admitted inpatient for continued observation.

Discussion
Methemoglobin refers to a variant of hemoglobin that undergoes oxidation, leading to a transition in its heme iron configuration from the ferrous fe2+ to the ferric fe3+ state.This state of hemoglobin lacks oxygen-carrying capacity and in good health is normally present in less than 1% of the blood concentration (the normal range has been described as 1-3% in some sources). 1uring red blood cell metabolism, methemoglobin is formed and converted back to its normal ferrous state at low levels.The process of methemoglobin production and reduction is typically balanced to uphold a steady-state level, which is around 1% of the total hemoglobin content (Figure 3).
Methemoglobinemia describes an imbalance in this equilibrium leading to Methemoglobin levels above the normal 1-3%.Hemoglobin deoxygenation, reactions with endogenous free radicals and exogenous chemicals can increase methemoglobin levels.Causes can be congenital or acquired (Table 1 and Box 1). 4 The failure of methemoglobin to effectively bind oxygen results in the inability to deliver oxygen to tissues.This condition presents a spectrum of symptoms and signs, ranging from simple cyanosis and the distinctive chocolate brown blood (10 to 20% MetHb concentration) to tachypnea, confusion, and syncope (MetHb concentration>30%). 4Central nervous system hypoxia with seizure and or coma, metabolic acidosis with dysrhythmia occurs for MetHb concentration more than 50% (Table 2).
Under normal physiological conditions, red blood cell enzyme cytochrome b5 reductase maintains low levels of methemoglobin.Hence, the primary cause of inherited methemoglobinemia is a congenital deficiency in cytochrome b5 reductase and is inherited in an autosomal recessive pattern. 2 Hemoglobin M disease is the other form of congenital methemoglobin and is inherited as an autosomal dominant defect. 5,6In Hemoglobin M disease, a mutation in the gene coding for one of the globin chains results in a substitution of a tyrosine amino acid for either the proximal (F 8 ) or the distal (E 7 ) histidine amino acid in the α, β, or γ chains.This mutation stabilizes the iron in Fe 3+ form.Most individuals with congenital methemoglobinemia show no symptoms apart from cyanosis.An alternative pathway for methemoglobin reduction, which is not physiologically active, uses nicotinamide adenine dinucleotide phosphate NADPH methemoglobin reductase.NADPH is generated by glucose 6 phosphate dehydrogenase G6PD and this pathway is only activated by extrinsic acceptors such as methylene blue.This requirement of G6PD explains why Methylene Blue therapy is ineffective in individuals with G6PD deficiency. 7ongenital methemoglobinemia has three primary genetic causes.The most frequent cause is a deficiency in the CYB5R3 enzyme (autosomal recessive disorder).Following that, two other causes are hemoglobin M disease (autosomal dominant disorder) and cytochrome B5 deficiency.Although congenital methemoglobinemia due to cytochrome b5 reductase deficiency is exceptionally rare, but the actual incidence is unknown.Interestingly, it appears to occur more frequently among Siberian Yakuts,   Athabaskans, Eskimos, and Navajo populations. 8,9These CYB5R3 deficiencies come in two types: type I, which affects only red blood cells, and type II, which occurs in all tissues.Patients with type I disease typically experience mild symptoms and have a normal lifespan.In contrast, those with type II disease exhibit cyanosis (bluish skin due to lack of oxygen), along with developmental delay, intellectual disability and other neurological manifestations, and have a significantly shorter lifespan. 1,10cquired methemoglobinemia can range from severe to even potentially fatal depending on the plasma level.It can be a medical emergency and the diagnostic clues include cyanosis; respiratory or neurologic symptoms out of proportion to pulse oximetry; dark red brownish to blue blood that does not turn red with oxygenation; and low pulse oximetry that does not improve with oxygen.These symptoms generally occur with a methemoglobin level of 10% and a level of more than 30% can be life-threatening.][13] Methylene blue is often administered (1-2mg/kg IV) to treat patients with methemoglobinemia however it should be avoided in patients with G6PD deficiency due to the risk of hemolysis.A previous study found that methylene blue did not improve methemoglobinemia in patients with Hb M. 14 Therapy with vitamin C can be considered when methylene blue is not indicated.Prophylactic preoperative methylene blue administration in a patient with congenital MetHb lowered the methemoglobin level significantly.This led to a notable rise in oxygen saturation, providing a greater safety margin against hypoxemia during the perioperative period.Alternatively, Hyperbaric oxygen (HBO) therapy was found an effective treatment in MetHb.HBO therapy inhibits the oxidation of hemoglobin by nitrite and reduces MetHb levels by approximately 8% per hour. 1,15nhalation of high concentrations of oxygen can be also used to treat methemoglobinemia and high arterial oxygen pressure should be maintained to minimize tissue hypoxia during induction of general anesthesia.Additionally, blood transfusion or exchange transfusion should be considered in patients with severe MetHb exceeding 70%. 6,16,17 Summary of recommendations for perioperative management of congenital methemoglobinemia is given in Figure 4. 18 There have been few reported cases of perioperative management of congenital methemoglobinemia in the literature.In this report, we have also summarized all the reported cases of congenital methemoglobinemia and anesthesia management (Table 3).
In our patient MetHb concentration was 37.8% and pH 7.337, PaO2 302 mm Hg, PaCO2 44 mm Hg, and oxyhemoglobin level of 63.4%.Oxygenation and ventilation with FiO2 at 100% were maintained and the intraoperative vital signs such as blood pressure and heart rate remained stable.Repeated blood gases were taken during the procedure to follow MetHb level and acid-base balance to decide methylene blue utilization (first line).

Not reported
The routine use of local anesthetic administration was prohibited and no Methylene Blue therapy was needed.Postoperatively, the MetHb level was still 37.8%.We admitted the patient for 24 hours for post-operative observation.He remained stable and was discharged home a day after the procedure.Genetic testing later revealed homozygosity for the cytochrome b5 reductase-3 enzyme leading to cytochrome b5 reductase deficiency.

Conclusion
In conclusion, although congenital methemoglobinemia is rare, it is still life-threatening and therefore warrants strong perioperative consideration.Patients with congenital or inherited methemoglobinemia pose a challenge with respect to perioperative management of oxygenation and global tissue perfusion.
The avoidance of potential oxidizing agents as well as the availability of emergency treatment such as methylene blue or exchange transfusion and hyperbaric oxygen therapy should be discussed.A card with a list of contraindicated medications could be given to the patient to prevent the patient's future exposure and disease exacerbation.
Intraoperatively the anesthesiologist should discuss the safety precautions with the nursing and surgical team.The use of oxidizing agents must be avoided and oxygen carrying capacity must be maintained by ensuring high oxygen concentration in the inhaled gases.Methylene blue can be given prophylactically or as therapy, if the patient has a normal G6PD level.The decision to treat or not is ideally guided by clinical judgment and serial blood gases to check MetHb level, oxyhemoglobin, and acid-base balance can be used to support clinical findings.Blood transfusion or exchange transfusion can also be considered.A hyperbaric oxygen therapy chamber within the hospital facility might also be a great advantage.

Patient Consent
The patient provided written consent for the publication.

DovePress
Journal of Blood Medicine 2024:15 learning disability.Of note, two years prior, he underwent dental extraction in a dental clinic under local anesthesia, following which, he developed severe cyanosis later in his home, requiring hospital admission and intensive care unit management.

Figure 2
Figure 2 Patient had varying concentrations of MetHb with values from 1 to 44.5%.

Figure 3
Figure 3 Equilibrium of Met Hb and Normal Hb in the body.

Figure 4
Figure 4 Recommendations for Perioperative Management of Congenital Methemoglobinemia.Notes: *Stable patient refers to an asymptomatic, hemodynamically stable patient.Such patients can be monitored in the PACU with frequent measurement of methemoglobin levels and standard care.

Table 1
Causes of Congenital Methemoglobinemia

Table 2
2ymptoms and Signs in a Patient with Methemoglobinemia (Adopted from Ludlow et al).2

Table 3
Summary of Reported Cases of Perioperative Management of Congenital Methemoglobinemia